The regenerative response of peripheral nervous system neurons (PNS) neurons to axotomy is the central feature of the restoration of the PNS after injury and one of the best-characterized examples of neural plasticity. Surprisingly, little is known about signaling mediators that are either required or instructive for regrowth of the axon. Neuronal growth factors are logical candidates to be regulators for peripheral axon regeneration. However, it remains unclear whether the same signaling molecules that have recently been identified as mediating morphological responses to growth factors during development also mediate axon growth after injury. Primary sensory neurons of the dorsal root ganglia are an ideal system in which to explore these issues. DRG neurons elaborate both a peripheral process that readily regenerates after injury and a central process that does not. In preliminary data employing an in vitro model system, we show that regenerative axon growth is mediated via different signaling mechanisms than developmental axon growth. We now plan to confirm this result and test this idea in vivo by generating several strains of mutant mice where key neurotrophin and cytokine signaling mediators have been conditionally inactivated in sensory neurons. The following Specific Aims will be carried out: 1. Compare the role of neurotrophin and cytokine signaling mediators in developmental versus regenerative sensory axon growth. Our hypothesis based on preliminary results is that regenerative axon growth of adult neurons is mediated by different signaling mechanisms than developmental axon growth of embryonic neurons. 2. Assess sensory axon regeneration in mice where key neurotrophin and cytokine signaling mediators have been conditionally mutated. Our hypothesis based on in vitro studies is that cytokine signaling is critical to PNS axon regeneration. 3. Assess enhancement of CNS regeneration in mice expressing inducible, activated neurotrophin and cytokine signaling mediators. Our hypothesis is that augmentation of receptor tyrosine kinase and cytokine signaling will promote robust regeneration of the central process in the spinal cord after dorsal column lesions. Defining signaling mediators of regenerative axon growth will critically inform strategies to promote regrowth of axons after spinal cord injuries in humans.